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Littermates
Kinds of Littermates Terms modified by Littermates Selected AbstractsBrief exposure to the biological mother "potentiates" the isolation behavior of precocial Guinea pig pupsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 8 2006Michael B. Hennessy Abstract When isolated rat pups are briefly reunited with a lactating female, her subsequent removal leads to a dramatic increase in the emission of ultrasonic vocalizations, but not other behaviors. Whether this socially induced augmentation of isolation behavior (i.e., "potentiation") is characteristic only of altricial rodents is not known. Therefore, we examined precocial guinea pig pups in a potentiation paradigm. Ten-day-old guinea pigs were isolated in a test cage for 10 min, at which time they were then placed into a second cage for 5 min that either contained a companion or, for controls, was empty. Pups were then isolated again in the test cage for a second 10-min period. Control pups showed a significant reduction in vocalizing and locomotor activity from the first to second isolation period. Exposure to the biological mother prevented the decline in both behaviors (Experiment 1), whereas exposure to a familiar littermate (Experiment 2) had no effect, and exposure to an unfamiliar lactating female (Experiment 3) had only a minimal effect on locomotor activity. The results show that potentiation of isolation behaviors is not limited to altricial rodents, and suggest that specific characteristics of the effect (i.e., its magnitude, the specific behaviors affected, and the selectivity of the response to particular social partners) varies with the abilities and requirements of the young, as well as the behavioral ecology of the species in question. © 2006 Wiley Periodicals, Inc. Dev Psychobiol 48: 653,659, 2006. [source] Maternal and littermate deprivation disrupts maternal behavior and social-learning of food preference in adulthood: Tactile stimulation, nest odor, and social rearing prevent these effectsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 3 2006Angel I. Melo Abstract Maternal and littermate (social) separation, through artificial rearing (AR), disrupts the development of subsequent maternal behavior and social learning in rats. The addition of maternal-licking-like stimulation during AR, partially reverses some of these effects. However, little is know about the role of social stimuli from littermates and nest odors during the preweaning period, in the development of the adult maternal behavior and social learning. The purpose of this study was to examine the effects of peer- and peer-and-odor rearing on the development of maternal behavior and social learning in rats. Female pups were reared with mothers (mother reared,MR) or without mothers (AR) from postnatal day (PND) 3. AR rats received three different treatments: (1) AR-CONTROL group received minimal tactile stimulation, (2) AR-ODOR females received exposure to maternal nest material inside the AR-isolation-cup environment, (3) AR-SOCIAL group was reared in the cup with maternal nest material and a conspecific of the same-age and same-sex and received additional tactile stimulation. MR females were reared by their mothers in the nest and with conspecifics. In adulthood, rats were tested for maternal behavior towards their own pups and in a social learning task. Results confirm our previous report that AR impairs performance of maternal behavior and the development of a social food preference. Furthermore, social cues from a littermate, in combination with tactile stimulation and the nest odor, reversed the negative effects of complete isolation (AR-CONTROL) on some of the above behaviors. Exposure to the odor alone also had effects on some of these olfactory-mediated behaviors. These studies indicate that social stimulation from littermates during the preweaning period, in combination with odor from the nest and tactile stimulation, contributes to the development of affiliative behaviors. © 2006 Wiley Periodicals, Inc. Dev Psyshobiol 48: 209,219, 2006. [source] Synaptic plasticity in the basolateral amygdala in transgenic mice expressing dominant-negative cAMP response element-binding protein (CREB) in forebrainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2000G. Rammes Abstract Electrophysiological and behavioural experiments were performed in transgenic mice expressing a dominant-negative form of cAMP response element-binding protein (CREBA133) in the limbic system. In control littermate in vitro slice preparation, tetanizing the lateral amygdala,basolateral amygdala (BLA) pathway with a single train (100 Hz for 1 s) produced short-term potentiation (STP) in the BLA. Five trains (10-s interstimulus interval) induced long-term potentiation (LTP), which was completely blocked by the N-methyl- d -aspartate (NMDA) receptor antagonist d(,)-2-amino-5-phosphonopentanoic acid (AP5; 50 ,m). When GABAergic (,-aminobutyric acid) inhibition was blocked by picrotoxin (10 ,m), LTP became more pronounced. Low-frequency stimulation (1 Hz for 15 min) induced either long-term depression (LTD) or depotentiation. LTD remained unaffected by AP5 (50 ,m) or by the L- and T-type Ca2+ -channel blockers nifedipine (20 ,m) and Ni2+ (50 ,m), but was prevented by picrotoxin (10 ,m), indicating a GABAergic link in the expression of LTD in the BLA. When conditioned fear was tested, a mild impairment was seen in one of three transgenic lines only. Although high levels of mRNA encoding CREBA133 lead to downregulation of endogenous CREB, expression of LTP and depotentiation were unaltered in BLA of these transgenic animals. These results could suggest that residual CREB activity was still present or that CREB per se is dispensable. Alternatively, other CREB-like proteins were able to compensate for impaired CREB function. [source] Schwann cell myelination occurred without basal lamina formation in laminin ,2 chain-null mutant (dy3K/dy3K) miceGLIA, Issue 2 2001Masahiro Nakagawa Abstract The laminin ,2 chain is a major component of basal lamina in both skeletal muscle and the peripheral nervous system. Laminin ,2 chain deficiency causes merosin-deficient congenital muscular dystrophy, which affects not only skeletal muscles, but also the peripheral and central nervous systems. It has been reported that the formation of basal lamina is required for myelination in the peripheral nervous system. In fact, the spinal root of dystrophic mice (dy/dy mice), whose laminin ,2 chain expression is greatly reduced, shows lack of basal lamina and clusters of naked axons. To investigate the role of laminin ,2 chain and basal lamina in vivo, we examined the peripheral nervous system of dy3K/dy3Kmice, which are null mutants of laminin ,2 chain. The results indicate the presence of myelination although Schwann cells lacked basal lamina in the spinal roots of dy3K/dy3K mice, suggesting that basal lamina is not an absolute requirement for myelination in vivo. Immunohistochemically, the expression of laminin ,4 chain was increased and laminin ,5 chain was preserved in the endoneurium of the spinal root. Laminin ,4 and ,5 chains may play the critical role in myelination instead of laminin ,2 chain in dy3K/dy3Kmice. In addition, the motor conduction velocity of the sciatic nerve was significantly reduced compared with that of wild-type littermate. This reduction in conduction velocity may be due to small axon diameter, thin myelin sheath and the patchy disruption of the basal lamina of the nodes of Ranvier in dy3K/dy3Kmice. GLIA 35:101,110, 2001. © 2001 Wiley-Liss, Inc. [source] Fetal programming of fat and collagen in porcine skeletal musclesJOURNAL OF ANATOMY, Issue 6 2005J. F. Karunaratne Abstract Connective tissue plays a key role in the scaffolding and development of skeletal muscle. Pilot studies carried out in our laboratory have shown that the smallest porcine littermate has a higher content of connective tissue within skeletal muscle compared with its largest littermate. The present study investigated the prenatal development of intralitter variation in terms of collagen content within connective tissue and intramuscular fat of the M. semitendinosus. Twenty-three pairs of porcine fetuses from a Large White,Landrace origin were used aged from 36 to 86 days of gestation. The largest and smallest littermates were chosen by weight and the M. semitendinosus was removed from each. Complete transverse muscle sections were stained with Oil Red O (detection of lipids) and immunocytochemistry was performed using an antibody to collagen I. Slides were analysed and paired t -Tests revealed the smallest littermate contained a significantly higher proportion of fat deposits and collagen I content compared with the largest littermate. Recent postnatal studies showing elevated levels of intramuscular lipids and low scores for meat tenderness in the smallest littermate corroborate our investigations. It can be concluded that the differences seen in connective tissue elements have a fetal origin that may continue postnatally. [source] Galanin Knockout Mice Show Disturbances in Ethanol Consumption and Expression of Hypothalamic Peptides That Stimulate Ethanol IntakeALCOHOLISM, Issue 1 2010Olga Karatayev Background:, There is growing evidence suggesting that hypothalamic galanin (GAL), which is known to stimulate intake of a fat-rich diet, has a role in promoting the consumption of ethanol. The present study further examined this possibility in GAL knockout (GALKO) mice. Methods:, Two groups of female and male GALKO mice, compared to wild-type (WT) controls, were trained to voluntarily drink increasing concentrations of ethanol, while maintained on lab chow and water. They were examined in terms of their daily ethanol intake and preference, acute consumption of a high-fat diet, preference for flavored solutions, and expression of different peptides shown to stimulate ethanol intake. Results:, In the GALKO mice compared to WT, the results revealed: (i) a 35 to 45% decrease in ethanol intake and preference, which was evident only at the highest (15%) ethanol concentration, was stronger in female than in male mice, and was seen with comparisons to littermate as well as nonlittermate WT mice; (ii) a 48% decrease in acute intake of a fat-rich diet, again stronger in female than male mice; (iii) no difference in consumption of sucrose or quinine solutions in preference tests; (iv) a total loss of GAL mRNA in the hypothalamic paraventricular nucleus (PVN) of female and male mice; and (v) a gender-specific change in mRNA levels of peptides in the perifornical lateral hypothalamus (PFLH), orexin and melanin-concentrating hormone, which are known to stimulate ethanol and food intake and were markedly decreased in females while increased in males. Conclusions:, These results provide strong support for a physiological role of PVN GAL in stimulating the consumption of ethanol, as well as a fat-rich diet. Ablation of the GAL gene produced a behavioral phenotype, particularly in females, which may reflect the functional relationship of galanin to ovarian steroids. It also altered the peptides in the PFLH, with their reduced expression contributing to the larger behavioral effects observed in females and their increased expression attenuating these effects in males. [source] Characterization of sleep,wake patterns in a novel transgenic mouse line overexpressing human prepro-orexin/hypocretinACTA PHYSIOLOGICA, Issue 3 2010K. A. Mäkelä Abstract Aim:, Orexin/hypocretin peptides are expressed in the lateral hypothalamus and involved in the regulation of autonomic functions, energy homeostasis and arousal states. The sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and occurrence of sudden rapid eye movement (REM) sleep, is associated with a loss of orexin neurones. Our study investigated the effects of orexins on sleep,wake patterns in a novel transgenic mouse line overexpressing the human prepro-orexin (hPPO) gene under the control of its endogenous promoter. Methods:, Orexin overexpression was investigated by PCR, Southern and Western blotting as well as immunohistochemistry. Polysomnographic recordings were performed for analyses of sleep,wake patterns and for electroencephalographic activity during 24 h baseline and during and after 6 h of sleep deprivation (SD). Results:, Transgenic hPPO mice had increased expression of human prepro-orexin (hPPO) and orexin-A in the hypothalamus. Transgene expression decreased endogenous orexin-2 receptors but not orexin-1 receptors in the hypothalamus without affecting orexin receptor levels in the basal forebrain, cortex or hippocampus. Transgenic mice compared with their wild type littermates showed small but significant differences in the amount of waking and slow wave sleep, particularly during the light,dark transition periods, in addition to a slight reduction in REM sleep during baseline and during recovery sleep after SD. Conclusion:, The hPPO-overexpressing mice show a small reduction in REM sleep, in addition to differences in vigilance state amounts in the light/dark transition periods, but overall the sleep,wake patterns of hPPO-overexpressing mice do not significantly differ from their wild type littermates. [source] Analysis of pancreatic endocrine development in GDF11-deficient miceDEVELOPMENTAL DYNAMICS, Issue 11 2006Darwin S. Dichmann Abstract Here, we examine the role of GDF11 in pancreatic development. Using in situ hybridization and reverse transcriptase-polymerase chain reaction analyses, we show that Gdf11 transcripts are expressed in embryonic pancreas epithelium before the secondary transition but decrease rapidly afterward. To determine the function of GDF11 during pancreas development, we analyzed Gdf11,/, mouse embryos. In such embryos, pancreas size is twofold reduced at embryonic day (E) 18 compared with wild-type littermates. Quantification of the different tissue compartments shows a specific hypoplasia of the exocrine compartment, while the endocrine and ductal compartments are unaffected. Notably, NGN3+ endocrine precursor cells are increased fourfold at E18, although the amount of endocrine cells in the pancreas of these animals is unchanged compared with wild-type littermates. Similarly, the maturation of endocrine cells as well as the ratio between ,- and ,-cells appears normal. Developmental Dynamics 235:3016,3025, 2006. © 2006 Wiley-Liss, Inc. [source] Dopamine's role in social modulation of infant isolation-induced vocalization: I. Reunion responses to the dam, but not littermates, are dopamine dependentDEVELOPMENTAL PSYCHOBIOLOGY, Issue 2 2009Harry N. Shair Abstract Rat pups' vocalization during social separation and the cessation of vocalization upon social reunion (contact quieting) model early life affiliative relationships. The present study examined the roles of dopamine (DA) receptors in regulating contact quieting. Contact quieting to the dam, but not to littermates, was disrupted by either blockade or exogenous stimulation of DA D1-like receptors. The D2 antagonist raclopride also prevented the quieting effect of reunion with the dam and had a lesser effect on the quieting properties of littermates. In contrast, the D2 agonist quinpirole permitted or enhanced contact quieting. Combined systemic and local striatal administration of D2 ligands showed that stimulation of striatal D2 receptors can enhance, but is not necessary for, contact quieting to the dam. These results are consistent with the literature linking the neural mechanisms of affiliation and reinforcement. This is also the first demonstration that the neurochemical substrates of an infant comfort response to dams differ from a behaviorally similar response to siblings. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 51: 131,146, 2009 [source] Differential development of body equilibrium among littermates in the newborn rabbitDEVELOPMENTAL PSYCHOBIOLOGY, Issue 1 2009Edith Muciño Abstract Interest is growing among psychobiologists and behavioral ecologists in the role of sibling relations in shaping individual development and life histories. In litters of domestic rabbits Oryctolagus cuniculus the heaviest pups at birth are more likely to survive the critical first postnatal week, they compete more effectively with littermates for milk and well-insulated positions in the litter huddle, and are the heaviest at weaning. Here we report that high birth weight pups are also better able to maintain body equilibrium. Testing pups' ability to maintain equilibrium when placed on a 15° ramp for 2 min each day during the first postnatal week, we found that pups showed a continual daily improvement in their ability to maintain balance while moving on the ramp, rarely lost balance by postnatal day 8, and that heavier pups could maintain balance better and earlier than their lighter littermates. Better ability to maintain body equilibrium, however achieved, may help explain heavier pups' advantage in competing for vital resources such as milk and in gaining access to better-insulated positions in the litter huddle. It also provides further support for the usefulness of birth weight, not only as an absolute measure but also relative to the weight of other littermates, as a predictor of different developmental trajectories, behavioral and physiological, among same-age siblings in this mammal. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 51: 24,33, 2009 [source] Effects of neonatal novelty exposure on sexual behavior, fear, and stress-response in adult ratsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 3 2007Fernando Benetti Abstract Environmental stimuli in early life may result in permanent behavioral and physiological changes. Present study evaluated the effects of exposing pups to a novel environment on behaviors (open-field test and sexual behavior) and prolactin stress-responses in adult male rats. Half of a litter was daily removed outside (OUT) from the nest and stimulated by handling for 3 min, while the other half remained inside (IN) the nest and was also handled for the same period during the first 10 days postpartum. Maternal behavior after all the pups were returned to the nest was not different between IN and OUT littermates. In adulthood, OUT males showed increased general and central locomotion activity in the open-field test, reduced sexual behavior, and attenuated prolactin secretion in response to restraint stress compared with the IN littermates. The repeated exposition of rat pups to a novel environment is a causal factor for the long-lasting behavioral and endocrine changes. The premature exposition of the pup to unfamiliar environments decreases fear and stress-response, and also reduces sexual behavior. We suggest that the absence of the odor of the mother may be crucial to explain the effects detected in adulthood. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 258,264, 2007. [source] Maternal and littermate deprivation disrupts maternal behavior and social-learning of food preference in adulthood: Tactile stimulation, nest odor, and social rearing prevent these effectsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 3 2006Angel I. Melo Abstract Maternal and littermate (social) separation, through artificial rearing (AR), disrupts the development of subsequent maternal behavior and social learning in rats. The addition of maternal-licking-like stimulation during AR, partially reverses some of these effects. However, little is know about the role of social stimuli from littermates and nest odors during the preweaning period, in the development of the adult maternal behavior and social learning. The purpose of this study was to examine the effects of peer- and peer-and-odor rearing on the development of maternal behavior and social learning in rats. Female pups were reared with mothers (mother reared,MR) or without mothers (AR) from postnatal day (PND) 3. AR rats received three different treatments: (1) AR-CONTROL group received minimal tactile stimulation, (2) AR-ODOR females received exposure to maternal nest material inside the AR-isolation-cup environment, (3) AR-SOCIAL group was reared in the cup with maternal nest material and a conspecific of the same-age and same-sex and received additional tactile stimulation. MR females were reared by their mothers in the nest and with conspecifics. In adulthood, rats were tested for maternal behavior towards their own pups and in a social learning task. Results confirm our previous report that AR impairs performance of maternal behavior and the development of a social food preference. Furthermore, social cues from a littermate, in combination with tactile stimulation and the nest odor, reversed the negative effects of complete isolation (AR-CONTROL) on some of the above behaviors. Exposure to the odor alone also had effects on some of these olfactory-mediated behaviors. These studies indicate that social stimulation from littermates during the preweaning period, in combination with odor from the nest and tactile stimulation, contributes to the development of affiliative behaviors. © 2006 Wiley Periodicals, Inc. Dev Psyshobiol 48: 209,219, 2006. [source] Retarded kindling progression in mice deficient in the extracellular matrix glycoprotein tenascin-REPILEPSIA, Issue 4 2009Katrin Hoffmann Summary Purpose:, We investigated the role of the extracellular matrix glycoprotein tenascin-R (TNR) in formation of a hyperexcitable network in the kindling model of epilepsy. The idea that TNR may be important for this process was suggested by previous studies showing that deficiency in TNR leads to abnormalities in synaptic plasticity, perisomatic GABAergic inhibition and more astrocytes in the hippocampus of adult mice. Methods:, Constitutively TNR deficient (TNR,/,) mice and their wild-type littermates received repeated electrical stimulation in the amygdala over several days until they developed fully kindled generalized seizures at which time their brains were studied immunohistochemically. Results:, In TNR,/, mice, kindling progression was retarded compared with wild-type littermate controls. Morphological analysis of the mice used for the kindling studies revealed that, independently of genotype, numbers of parvalbumin-positive interneurons in the dentate gyrus correlated positively with afterdischarge threshold alterations in kindled mice. The kindling-induced increase in the number of S100 expressing astrocytes in the dentate gyrus was enhanced by TNR deficiency and correlated negatively with the kindling rate. Discussion:, Our data support the view that TNR promotes formation of a hyperexcitable network during kindling and suggest that an increase in S100-expressing astrocytes may contribute to retarded epileptogenesis in TNR,/, mice. [source] Mice Carrying the Szt1 Mutation Exhibit Increased Seizure Susceptibility and Altered Sensitivity to Compounds Acting at the M-ChannelEPILEPSIA, Issue 9 2004James F. Otto Summary:,Purpose: Mutations in the genes that encode subunits of the M-type K+ channel (KCNQ2/KCNQ3) and nicotinic acetylcholine receptor (CHRNA4) cause epilepsy in humans. The purpose of this study was to examine the effects of the Szt1 mutation, which not only deletes most of the C-terminus of mouse Kcnq2, but also renders the Chnra4 and Arfgap-1 genes hemizygous, on seizure susceptibility and sensitivity to drugs that target the M-type K+ channel. Methods: The proconvulsant effects of the M-channel blocker linopirdine (LPD) and anticonvulsant effects of the M-channel enhancer retigabine (RGB) were assessed by electroconvulsive threshold (ECT) testing in C57BL/6J- Szt1/+ (Szt1) and littermate control C57BL/6J+/+ (B6) mice. The effects of the Szt1 mutation on minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures were evaluated by varying stimulation intensity and frequency. Results:Szt1 mouse seizure thresholds were significantly reduced relative to B6 littermates in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Mice were injected with LPD and RGB and subjected to ECT testing. In the minimal clonic seizure model, Szt1 mice were significantly more sensitive to LPD than were B6 mice [median effective dose (ED50) = 3.4 ± 1.1 mg/kg and 7.6 ± 1.0 mg/kg, respectively]; in the partial psychomotor seizure model, Szt1 mice were significantly less sensitive to RGB than were B6 mice (ED50= 11.6 ± 1.4 mg/kg and 3.4 ± 1.3 mg/kg, respectively). Conclusions: These results suggest that the Szt1 mutation alters baseline seizure susceptibility and pharmacosensitivity in a naturally occurring mouse model. [source] Obesity predisposes to Th17 biasEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2009Shawn Winer Abstract Obesity is associated with numerous inflammatory conditions including atherosclerosis, autoimmune disease and cancer. Although the precise mechanisms are unknown, obesity-associated rises in TNF-,, IL-6 and TGF-, are believed to contribute. Here we demonstrate that obesity selectively promotes an expansion of the Th17 T-cell sublineage, a subset with prominent pro-inflammatory roles. T-cells from diet-induced obese mice expand Th17 cell pools and produce progressively more IL-17 than lean littermates in an IL-6-dependent process. The increased Th17 bias was associated with more pronounced autoimmune disease as confirmed in two disease models, EAE and trinitrobenzene sulfonic acid colitis. In both, diet-induced obese mice developed more severe early disease and histopathology with increased IL-17+ T-cell pools in target tissues. The well-described association of obesity with inflammatory and autoimmune disease is mechanistically linked to a Th17 bias. [source] Lung CD11c+ cells from mice deficient in Epstein-Barr virus-induced gene,3 (EBI-3) prevent airway hyper-responsiveness in experimental asthmaEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2007Michael Hausding Abstract Epstein-Barr virus-induced gene (EBI)-3 codes for a soluble type,1 cytokine receptor homologous to the p40 subunit of IL-12 that is expressed by antigen-presenting cells following activation. Here, we analyzed the functional role of EBI-3 in a murine model of asthma associated with airway hyper-responsiveness (AHR) in ovalbumin-sensitized mice. Upon allergen challenge, EBI-3,/, mice showed less severe AHR, decreased numbers and degranulation of eosinophils and a significantly reduced number of VCAM-1+ cells in the lungs as compared to wild-type littermates. We thus analyzed lung CD11c+ cells before and after allergen challenge in these mice and found that before allergen challenge, lung CD11c+ cells isolated from EBI-3,/, mice express markers of a more plasmacytoid phenotype without releasing IFN-, as compared to those from wild-type littermates. Moreover, allergen challenge induced the development of myeloid CD11c+ cells in the lungs of EBI-3,/, mice, which released increased amounts of IL-10 and IL-12 while not expressing IFN-,. Finally, inhibition of EBI-3 expression in lung DC could prevent AHR in adoptive transfer studies by suppressing mediator release of effector cells into the airways. These results indicate a novel role for EBI-3 in controlling local immune responses in the lungs in experimental asthma. [source] Mast cells play a key role in the developmentof late airway hyperresponsiveness through TNF-,in a murine model of asthmaEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007Young-Suk Kim Abstract We have investigated the role of TNF-, in mast cell-mediated late airway hyperresponsiveness (AHR) using mast cell-deficient WBB6F1- W/Wv (W/Wv) mice in a murine model of asthma, which exhibits a biphasic increase in AHR. TNF-, levels in the airway and magnitude of late AHR in response to airway allergen challenge were severely impaired in W/Wv mice compared to their littermates. In addition to TNF-,, cytosolic phospholipase A2 (cPLA2) phosphorylation and enzymatic activity in the lungs were also impaired in W/Wv mice. Either anti-TNF-, antibody or an inhibitor of cPLA2 abolished late AHR in congeneic +/+ mice. Intratracheal administration of TNF-, resulted in increases in late AHR, cPLA2 phosphorylation, cPLA2 activity, and phosphorylation of mitogen-activated protein kinases. Mast cell replacement restored airway TNF-, level, cPLA2 phosphorylation and enzymatic activity in the lungs as well as late AHR in W/Wv mice. These data indicate that mast cells play a key role in the development of late AHR through liberation of TNF-,. [source] Polymerase,, is up-regulated during the T,cell-dependent immune response and its deficiency alters developmental dynamics of spleen centroblastsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005Daniel Lucas Abstract Mammalian DNA polymerase,, (Pol,), preferentially expressed in secondary lymphoid organs, is shown here to be up-regulated in germinal centers after immunization. Alternative splicing appears to be part of Pol, regulation during an immune response. We generated Pol,-deficient mice that are viable and show no anatomical malformation or serious alteration in lymphoid populations, with the exception of an underrepresentation of the B,cell compartment. Young and aged homozygous Pol,,/, mice generated similar immune responses after immunization with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gammaglobulin (CGG), compared with their wild-type littermates. Nonetheless, the kinetics of development of the centroblast population showed significant differences. Hypermutation analysis of the rearranged heavy chain intron region in centroblasts isolated from NP-CGG-immunized Pol,,/, mice showed a similar quantitative and qualitative somatic mutation spectrum, but a lower representation of heavily mutated clones. These results suggest that although it is not a critical partner, Pol, modulates the in vivo somatic hypermutation process. [source] Peripheral T,cell tolerance occurs early during spontaneous prostate cancer development and can be rescued by dendritic cell immunizationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2005Elena Degl'Innocenti Abstract In the tumor-prone transgenic adenocarcinoma mouse prostate (TRAMP) mouse model we followed the fate of the immune response against the SV40 large T,antigen (Tag) selectively expressed in the prostate epithelium during the endogenous transformation from normal cells to tumors. Young (5,7-week-old) male TRAMP mice, despite a dim and patchy expression of Tag overlapping foci of mouse prostate intraepithelial neoplasia, displayed a strong Tag-specific cytotoxic T,lymphocyte (CTL) response after an intradermal injection of peptide-pulsed dendritic cells (DC). This response was weaker than the one found in vaccinated wild-type littermates, and was characterized by a reduced frequency and avidity of Tag-specific CTL. Early DC vaccination also subverted the profound state of peripheral tolerance typically found in TRAMP mice older than 9,10,weeks. The DC-induced CTL response indeed was still detectable in TRAMP mice of 16,weeks, and was associated with histology evidence of reduced disease progression. Our findings suggest that tumor antigens are handled as self antigens, and peripheral tolerance is associated with in situ antigen overexpression and cancer progression. Our data also support a relevant role for DC-based vaccines in controlling the induction of peripheral tolerance to tumor antigens. [source] Treatment of neonatal mice with Flt3 ligand leads to changes in dendritic cell subpopulations associated with enhanced IL-12 and IFN-, productionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2004Sabine Vollstedt Abstract Treatment with the hematopoietic growth factor Flt3 ligand (FL) increases DC numbers in neonatal mice and enhances their resistance against intracellular pathogens. Flow cytometric analysis showed the presence of conventional DC (cDC) and plasmacytoid pre-DC (pDC) in neonatal spleens from untreated and FL-treated mice. CD8, and MHC class,II expression on cDC and pDC was higher on DC from FL-treated mice than on DC from control littermates. After FL treatment, two additional subpopulations of DC-lineage cells were found that were able to produce IL-12 and IFN-,. The IL-12 production of cDC from FL-treated animals was more than 50-fold increased and their ability to stimulate T,cell proliferation was also increased. We conclude that the enhanced resistance against intracellular pathogens was due to increased numbers of DC-lineage cells and their increased ability to produce the essential cytokines. [source] Impaired lymphocyte development and function in Clast5/Stra13/DEC1-transgenic miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2004Mika Seimiya Abstract Clast5/Stra13/DEC1 is a member of the helix-loop-helix family of transcriptional repressors. We have previously shown that Clast5 is rapidly down-regulated upon B,cell activation and its overexpression inhibits cell cycle progression in B,lymphoma cells. In the present study, we show that Clast5 expression is developmentally regulated during B,cell differentiation, being expressed at theprogenitor B,cells, down-regulated at the precursor B,cells, elevated in immature and mature resting B,lymphocytes, and down-regulated again in germinal center B,ells. To investigate the function of Clast5 in regulating lymphocyte development, we have generated transgenic mice expressing Clast5 in B- and T-lineage cells (Clast5-Tg). Clast5-Tg mice grew and bred normally but their spleen and thymus cellularity was reduced compared with control littermates. The development of B,cells in the bone marrow and T,cells in the thymus was impaired, with the expansion of progenitor B and T,cells most strongly affected. The frequency of IL-7-responsive cells in the bone marrow of Clast5-Tg mice was reduced by >80% and their proliferative response to IL-7 was also compromised. Mature B,cells from Clast5-Tg mice were hyporesponsive to antigen receptor cross-linking and exhibited mild reduction in the proliferative response to CD40 ligation or lipopolysaccharide stimulation. Moreover, thedevelopment of germinal center B,cells and antibody production against a T-dependent antigen were reduced in Clast5-Tg mice. These results reveal a critical role for Clast5/Stra13/DEC1 in negatively regulating lymphocyte development and function in vivo. [source] Cooperation between toll-like receptor,2 and,4 in the brain of mice challenged with cell wall components derived from gram-negative and gram-positive bacteriaEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2003Nathalie Laflamme Abstract In this study we investigated whether induction of toll-like receptor,2 (TLR2) amplifies the effect of a cell wall component derived from gram-positive bacteria, namely peptidoglycan (PGN). Mice received a first systemic lipopolysaccharide (LPS) injection to pre-induce TLR2 in various regions of the brain, and 6,h later, a second administration of either LPS or PGN. The data show a robust transcriptional activation of TLR2, TNF-, and monocyte chemotactic protein-1 (MCP-1) in microglial cells of mice challenged twice with LPS, whereas PGN essentially abolished this response. TLR4 plays a critical role in this process, because C3H/HeJ mice no longer responded to LPS but exhibited a normal reaction to PGN. Conversely, a robust signal for genes encoding innate immune proteinswas found in the brain of TLR2-deficient mice challenged with LPS. However, the second LPS bolus failed to trigger TNF-, and IL-12 in TLR2-deficient mice, while the same treatment caused a strong induction of these genes in the cerebral tissue of wild-type littermates. The present data provide evidence that cooperation exists between TLR4 and TLR2. While TLR4 is absolutely necessary to engage the innate immune response in the brain, TLR2 participates in the regulation of genes encoding TNF-, and IL-12 during severe endotoxemia. Such collaboration between TLR4 and TLR2 may be determinant for the transfer from the innate to the adaptive immunity within the CNS of infected animals. [source] Inactivation of astroglial NF-,B promotes survival of retinal neurons following ischemic injuryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2009Galina Dvoriantchikova Abstract Reactive astrocytes have been implicated in neuronal loss following ischemic stroke. However, the molecular mechanisms associated with this process are yet to be fully elucidated. In this work, we tested the hypothesis that astroglial NF-,B, a key regulator of inflammatory responses, is a contributor to neuronal death following ischemic injury. We compared neuronal survival in the ganglion cell layer (GCL) after retinal ischemia-reperfusion in wild-type (WT) and in GFAP-I,B,-dn transgenic mice, where the NF-,B classical pathway is suppressed specifically in astrocytes. The GFAP-I,B,-dn mice showed significantly increased survival of neurons in the GCL following ischemic injury as compared with WT littermates. Neuroprotection was associated with significantly reduced expression of pro-inflammatory genes, encoding Tnf-,, Ccl2 (Mcp1), Cxcl10 (IP10), Icam1, Vcam1, several subunits of NADPH oxidase and NO-synthase in the retinas of GFAP-I,B,-dn mice. These data suggest that certain NF-,B-regulated pro-inflammatory and redox-active pathways are central to glial neurotoxicity induced by ischemic injury. The inhibition of these pathways in astrocytes may represent a feasible neuroprotective strategy for retinal ischemia and stroke. [source] Olfactory deficits in mice overexpressing human wildtype ,-synucleinEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2008Sheila M. Fleming Abstract Accumulation of ,-synuclein in neurons of the central and peripheral nervous system is a hallmark of sporadic Parkinson's disease (PD) and mutations that increase ,-synuclein levels cause familial PD. Transgenic mice overexpressing ,-synuclein under the Thy1 promoter (Thy1-aSyn) have high levels of ,-synuclein expression throughout the brain but no loss of nigrostriatal dopamine neurons up to 8 months, suggesting that they may be useful to model pre-clinical stages of PD. Olfactory dysfunction often precedes the onset of the cardinal motor symptoms of PD by several years and includes deficits in odor detection, discrimination and identification. In the present study, we measured olfactory function in 3- and 9-month-old male Thy1-aSyn mice with a buried pellet test based on latency to find an exposed or hidden odorant, a block test based on exposure to self and non-self odors, and a habituation/dishabituation test based on exposure to non-social odors. In a separate group of mice, ,-synuclein immunoreactivity was assessed in the olfactory bulb. Compared with wildtype littermates, Thy1-aSyn mice could still detect and habituate to odors but showed olfactory impairments in aspects of all three testing paradigms. Thy1-aSyn mice also displayed proteinase K-resistant ,-synuclein inclusions throughout the olfactory bulb. These data indicate that overexpression of ,-synuclein is sufficient to cause olfactory deficits in mice similar to that observed in patients with PD. Furthermore, the buried pellet and block tests provided sufficient power for the detection of a 50% drug effect, indicating their usefulness for testing novel neuroprotective therapies. [source] Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Jared Clarke Abstract Cerebral ischaemia leads to a transient accumulation of ,-amyloid precursor protein (APP) and ,-amyloid (A,) peptides adjacent to the ischaemic lesion. There is conflicting evidence that APP/A, fragments may either enhance neuronal plasticity or be neurotoxic. The aim of the current study was to assess the effect of overexpression of human APP in rats on functional recovery following cerebral ischaemia. Adult APP-overexpressing (hAPP695 Tg) rats subjected to transient middle cerebral artery occlusion (MCAO) had significantly smaller infarct volumes than non-transgenic littermates, yet did not perform better on a series of sensorimotor or learning tests during a 6-month follow-up period. In fact, transgenic animals were found to be significantly more impaired in both the beam-walking and Morris water maze tests following MCAO. Immunohistochemistry showed human A,-positive staining in the cortex and hippocampus of APP transgenic rats. The present data suggest that while overexpression of APP in rats may provide some histological neuroprotection in the event of cerebral ischaemia, this does not translate into significant functional recovery. [source] Neuropathic pain is enhanced in ,-opioid receptor knockout miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006Xavier Nadal Abstract We have evaluated the possible involvement of ,-opioid receptor (DOR) in the development and expression of neuropathic pain. For this purpose, partial ligation of the sciatic nerve was performed in DOR knockout mice and wild-type littermates. The development of mechanical and thermal allodynia, as well as thermal hyperalgesia was evaluated by using the von Frey filament model, the cold-plate test and the plantar test, respectively. In wild-type and DOR knockout mice, sciatic nerve injury led to a neuropathic pain syndrome revealed in these nociceptive behavioural tests. However, the development of mechanical and thermal allodynia, and thermal hyperalgesia was significantly enhanced in DOR knockout mice. These results reveal the involvement of DOR in the control of neuropathic pain and suggest a new potential therapeutic use of DOR agonists. [source] Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2003Hong Li Abstract NB-2, a member of the contactin subgroup in the immunoglobulin superfamily, is expressed specifically in the postnatal nervous system, reaching a maximum level at 3 weeks postnatal. NB-2 displays neurite outgrowth-promoting activity in vitro. To assess its function in the nervous system, we generated mutant mice in which a part of the NB-2 gene was ablated and replaced with the tau-LacZ gene. The general appearance of NB-2-deficient mice and their gross anatomical features were normal. The LacZ expression patterns in heterozygous mice revealed that NB-2 is preferentially expressed in the central auditory pathways. In the audiogenic seizure test, NB-2-deficient mice exhibited a lower incidence of wild running, but a higher mortality rate than the wild-type littermates. c-Fos immunohistochemistry demonstrated that neural excitability induced by the audiogenic seizure test in the NB-2-deficient mice was prominently attenuated in both the dorsal and external cortices of the inferior colliculus, where enhanced neural excitability was observed in the wild-type mice. In response to pure-tone stimulation after priming, NB-2-deficient mice exhibited a diffuse and low level of c-Fos expression in the central nucleus of the inferior colliculus, which was distinctly different from the band-like c-Fos expression corresponding to the tonotopic map in the wild-type littermates. Taken together, these results suggest that a lack of NB-2 causes impairment of the neuronal activity in the auditory system. [source] Age-dependent cognitive decline in the APP23 model precedes amyloid depositionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2003Debby Van Dam Abstract Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6,8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-,1,42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-,1,42 peptides, but probe trial performance did correlate negatively with soluble amyloid-, brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model. [source] Morphological alterations in the amygdala and hippocampus of mice during ageingEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Oliver Von Bohlen und Halbach Abstract Declines in memory function and behavioural dysfunction accompany normal ageing in mammals. However, the cellular and morphological basis of this decline remains largely unknown. It was assumed for a long time that cell losses in the hippocampus accompany ageing. However, recent stereological studies have questioned this finding. In addition, the effect of ageing is largely unknown in another key structure of the memory system, the amygdala. In the present study, we have estimated neuronal density and total neuronal numbers as well as density of fragments of degenerated axons in different hippocampal subfields and amygdaloid nuclei. Comparisons were made among aged (21,26 months old) mice and normal adult littermates (8 months old). No significant volume loss occurs in the hippocampus of aged mice. Small but insignificant reductions in total neuronal numbers were found in the hippocampus and in the amygdaloid nuclei. In contrast to the mild effects of ageing upon neuronal numbers, fragments of degenerated axons were increased in both hippocampus and amygdala of aged mice. These data suggest that ageing does not induce prominent cell loss in the hippocampus or amygdala, but leads to degeneration of axons that innervate these forebrain structures. Thus, mechanisms underlying age-related dysfunction depend on parameters other than neuronal numbers, at least in the hippocampal formation and the amygdala. [source] Sexual dimorphism in the spontaneous recovery from spinal cord injury: a gender gap in beneficial autoimmunity?EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002Ehud Hauben Abstract Immune cells have been shown to contribute to spontaneous recovery from central nervous system (CNS) injury. Here we show that adult female rats and mice recover significantly better than their male littermates from incomplete spinal cord injury (ISCI). This sexual dimorphism is wiped out and recovery is worse in adult mice deprived of mature T cells. After spinal cord contusion in adult rats, functional recovery (measured by locomotor scores in an open field) was significantly worse in females treated with dihydrotestosterone prior to the injury than in placebo-treated controls, and significantly better in castrated males than in their noncastrated male littermates. Post-traumatic administration of the testosterone receptor antagonist flutamide promoted the functional recovery in adult male rats. These results, in line with the known inhibitory effect of testosterone on cell-mediated immunity, suggest that androgen-mediated immunosuppression plays a role in ISCI-related immune dysfunction and can therefore partly explain the worse outcome of ISCI in males than in female. We suggest that females, which are more prone to develop autoimmune response than males, benefit from this response in cases of CNS insults. [source] | ||||||||||||||||||||||||||||||||||